In man, normal urinary bladder contractions are mediated, in part, through cholinergic muscarinic receptor stimulation. Muscarinic receptors not only mediate, in part, normal bladder contractions, but may also mediate the main part of the contractions in the overactive bladder resulting in symptoms such as urinary frequency, urgency and urge urinary incontinence.
After administration of Fesoterodine and other phenolic monoesters of formula (I) to mammals, such as humans, these compounds are cleaved by esterases to form the Active Metabolite within the body. The Active Metabolite is known to be a potent and competitive muscarinic receptor antagonist (WO 94/11337). Fesoterodine and other phenolic esters of the formula (I) thus represent potential prodrugs for the Active Metabolite. Fesoterodine, in particular, has been shown to be an effective drug for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency, as well as detrusor hyperactivity (as described in U.S. Pat. No. 6,713,464 and EP-B-1,077,912).
A synthetic approach for the production of the Active Metabolite and monoesters of the phenolic hydroxy group of the Active Metabolite such as Fesoterodine has been described in U.S. Pat. No. 6,713,464 as follows:
In a first step, an ethereal solution is prepared from R-(−)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine, ethyl bromide and magnesium; this solution is diluted with dry THF and is cooled to −60° C.
In a second step, powdered solid carbon dioxide is added in small portions and the reaction mixture is warmed to room temperature.
In a third step, the reaction is quenched with an aqueous solution of ammonium chloride.
In a fourth step, the aqueous phase of the quenched reaction mixture is adjusted to a pH of 0.95.
In a fifth step, the pH adjusted aqueous phase is filtered and R-(−)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acid hydrochloride can be recovered from the solid.
In a sixth step, the resulting purified benzoic acid is esterified to its corresponding methyl ester.
In a seventh step, the methyl ester of step six is reduced by the addition of lithium aluminium hydride. After a reaction for 18 hours, the reaction is quenched with water and the organic phase is dried over sodium sulphate, filtered and evaporated to dryness to gain the alcohol that gradually crystallized from an oil.
A diagram summarizing this multi-step synthesis is shown below.
Steps 1 to 5:

Step 6:

Step 7:

U.S. Pat. No. 6,713,464 further describes converting the methyl ester to the Active Metabolite, and then esterifying the Active Metabolite to a phenolic monoester, such as Fesoterodine.
WO 94/11337 also describes a multi-stage process to synthesize the precursor of the Active Metabolite.
These previously described methods for producing the Active Metabolite require numerous steps that result in complex purification procedures, time-delay, and enhanced possibility of human error, thereby prohibiting optimal efficiency and cost-effectiveness. Also, the solid carbon dioxide used in the art is difficult to handle on large scale due to the need to work at very low temperatures and to add the crushed dry ice portionwise, and due to the difficulties to control the very exothermic nature of the reaction. Also, the reduction step with lithium aluminium hydride used in the prior art causes a significant amount of waste on large scale, which is disadvantageous both from an economical as well as from an ecological point of view.
The present disclosure aims to overcome these problems and disadvantages. Surprisingly, it has now been found that the use of paraformaldyde or trioxane in the Grignard reaction using a Grignard initiator in the presence of an excess of Mg, is suitable to directly obtain a compound of formula (III) without previously synthesizing the corresponding ester. The use of paraformaldehyde or trioxane results in a shortened synthetic route to Fesoterodine via a compound of formula (III) by eliminating the production of the benzoic acid and the methyl ester intermediates and provides an increased overall yield.

Accordingly, the use of paraformaldehyde or trioxane in the Grignard reaction initiated by the use of a Grignard initiator in the presence of extra Mg allows for a direct and more cost-effective synthetic approach to compounds of formula (I) via a compound of formula (III) thereby eliminating undesired side-products such as the benzoic acid derivatives, which often are formed when using an approach via the corresponding ester followed by a reduction step.